Total synthesis of (-)-ratjadone.
[reaction in text] A convergent asymmetric synthesis of (-)-ratjadone (1) has been achieved, confirming the assignments of stereochemistry for the naturally occurring antifungal metabolite.
Antifungal Agents↗
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Studies toward the total synthesis of scyphostatin: first entry to the highly functionalized cyclohexenone segment.
The cyclohexenone segment 2 of scyphostatin (1), a potent inhibitor of neutral sphingomyelinase, was synthesized in an enantioselective manner starting from the bromo ether 5 and D-serinal derivative 3. The synthetic method features a coupling reaction of 5 with 3 to construct the asymmetric quaternary carbon center and a stereospecific epoxide ring formation as the key steps.
Amides↗
Pseudo-C(3)-symmetric tertiary alcohol building block via group-selective hydroalumination: a synthesis of (-)-malyngolide.
The stereocontrolled preparation of tertiary alcohol 4 and its TMS surrogate 5, which share a pseudo-C(3)()-symmetry, is described. Compound 4 was used for the synthesis of (-)-malyngolide.
Alcohols↗
Synthesis of the C1-C12 fragment of fostriecin.
[reaction: see text] The synthesis of the C(1)-C(12) fragment of fostriecin was achieved from (S)-glycidol in 15 steps by using an enantioselective allytitanation reaction and a ring-closure metathesis as the key steps.
Alkenes↗
Efficient strategy for the synthesis of stereopentad subunits of scytophycin, rifamycin S, and discodermolide.
[reaction: see text] An efficient, simple method has been developed for the stereocontrolled synthesis of polypropionate stereopentads in high enantio- and diastereomeric purities.
Aldehydes↗
A short and efficient route to novel scyphostatin analogues.
[structure: see text]. Several novel scyphostatin analogues have been prepared in up to 18% yield over five steps from commercially available 4-bromoguaiacol, utilizing an organometallic addition to afford the desired syn-hydroxy-epoxides.
Amides↗
Stereoselective synthesis of functionalized trisubstituted olefins via palladium(0)-catalyzed cross-coupling reaction.
[reaction: see text]. A highly flexible and stereoselective protocol for the synthesis of branched (E)- and (Z)-trisubstituted alkenes has been developed. The key steps are hydrozirconation-iodination of (1-alkynyl)trimethylsilane followed by Negishi-type cross-coupling. The resultant (Z)-vinyl silane is iododesilylated and subjected to a second cross-coupling reaction to give the trisubstituted olefin. Model studies aimed at the construction of the C14-C15 (Z)-trisubstituted olefin of discodermolide and the C8-C9 (Z)-trisubstituted olefin of callystatin A and analogues are also described.
Alkanes↗
Studies on the biomimetic synthesis of SNF4435 C and D.
[reaction: see text] The biomimetic synthesis of the bicyclic core of the novel immunosuppresants SNF4435C and SNF4435D is reported. The core framework was efficiently generated from the all-trans tetraene precursor in one step and in good yield.
Molecular Mimicry↗
Formal total synthesis of fostriecin.
[reaction: see text] Addition of magnesium anion 4 (M = MgBr, R(1) = TES) to ketone 6 (R(2) = PMB) at -78 degrees C in THF proceeded under chelation control to provide alcohol 7, which possesses the full set of the chiral centers of fostriecin. Subsequently, 7 was transformed successfully to the known key intermediate 2.
Alcohols↗
Asymmetric total synthesis of (+)-fostriecin.
[structure: see text] The title compound, a potent protein phosphatase inhibitor and anticancer agent, was prepared by an efficient, multiconvergent asymmetric synthesis. Key transformations include a ring forming olefin metathesis leading to the alpha,beta-unsaturated lactone and creation of the triene moiety via Suzuki cross-coupling.
Alkenes↗
Total synthesis of (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A and (-)-(6S,7S,8S,9R,10S)- membrenone-B and structural assignment of membrenone-C.
[reaction: see text] (-)-(6S,7S,8S,9R,10S,2'S)-Membrenone-A and (-)-(6S,7S,8S,9R,10S)-membrenone-B were prepared in 11 steps (3% and 2.4% overall yield, respectively). Key steps included a tin(II)-mediated aldol followed by a syn selective reduction, giving the C7-C9 stereocenters, a second chain extending aldol coupling, and a p-TsOH-promoted cyclization/dehydration giving the common gamma-dihydropyrone precursor. We have thus established that synthetic (-)-(6S,7S,8S,9R,10S,2'S)-membrenone-A, (-)-(6S,7S,8S,9R,10S)-membrenone-B, and (-)-(6S,7S,8S,9R,10S)-membrenone-C are the enantiomers of the natural products.
Catalysis↗
Toward the combinatorial synthesis of polyketide libraries: asymmetric aldol reactions with alpha-chiral aldehydes on solid support.
[reaction: see text] The viability of performing stereocontrolled aldol additions with alpha-chiral aldehydes attached by a silyl linker to a hydroxymethylpolystyrene resin is demonstrated for boron and titanium enolates. Subsequent ketone reduction and manipulation on the solid support leads to elaborate stereopentad sequences, as occur in 6-deoxyerythronolide B and discodermolide.
Acetals↗
Synthetic studies toward SNF4435 C and SNF4435 D.
[reaction: see text] A synthetic approach toward the immunosuppressants SNF3345 C and SNF4435 D featuring a tandem Stille coupling/electrocyclization cascade is described.
Cyclization↗
Simultaneous preparation of four truncated analogues of discodermolide by fluorous mixture synthesis.
[structure: see text] Four truncated analogues of the natural product discodermolide were synthesized in a single synthetic sequence. Precursors bearing four different groups at C22, each with a unique fluorous p-methoxybenzyl substituent on the C17 hydroxy group, were mixed and taken through an nine-step sequence. Demixing by fluorous chromatography followed by deprotection and purification provided the individual analogues in 3-7% overall yields and with a savings of 24 synthetic steps. Fluorous mixture synthesis is recommended as a new technique to make multiple natural product analogues in a single multistep synthesis.
Alkanes↗
Studies directed toward the total synthesis of discodermolide: asymmetric synthesis of the C1-C14 fragment.
[structure: see text] A convergent and stereoselective assembly of the C1-C14 subunit of marine natural product (+)-discodermolide has been completed. The approach employs chiral allylsilane bond construction methodology to establish four of the eight stereogenic centers. Key fragment coupling is achieved via an efficient stereoselective acetate aldol reaction between C1-C6 and C7-C14 subunits.
Alkanes↗
Total synthesis of (+/-)-mycoepoxydiene, a novel fungal metabolite having an oxygen-bridged cyclooctadiene skeleton.
[reaction: see text] The first total synthesis of (+/-)-mycoepoxydiene has been accomplished. A ring-closing olefin metathesis (RCM) approach was employed for the construction of the oxygen-bridged eight-membered bicyclic skeleton. The RCM product was converted to the target natural product featuring the oxidative rearrangement of a furfuryl alcohol introduced as the side chain and the stereoselective 1,2-reduction of a delta-keto-beta,gamma-unsaturated alpha-lactol intermediate.
Bridged-Ring Compounds↗
Synthesis of enantiopure dihydropyranones: aldol-based ring expansion of dihydrofurans.
[reaction: see text] The stereoselective Birch reduction of 3-methyl-2-furoic acids using a readily available chiral auxilairy is described; by coupling this process to an oxidative cleavage/aldol ring closure sequence we were able to produce highly functionalized and enantiopure dihydropyranones in high yield. This sequence has ample flexibility built into it, either by the use of different electrophiles during reductive alkylation or by subsequent derivatization of the dihydropyranone after ring expansion.
Alkylation↗
The Synthesis of L-aminosugar and the studies of L-pyranoses on the ring III of pyranmycins.
The synthesis of a novel class of aminoglycoside, pyranmycin, and a convenient method for the preparation of 6-amino-L-idopyranosides were reported. One of the members in the reported pyranmycin families, TC010, has prominent activity against Escherichia coli, Staphylococcus aureus, and Bacillus megaterium. We also discovered that the (4)C(1) chair conformation on ring III of pyranmycin is essential for the antibacterial activity. [reaction: see text]
Amino Sugars↗